Cell adhesion molecules are generally identified as cadherins, integrins, selectins, or as members of the Immunoglobulin (Ig) superfamily. The immunoglobulin superfamily molecules include cell surface antigen receptors, co-receptors and co-stimulatory molecules of the immune system, molecules involved in antigen presentation to lymphocytes, cell adhesion molecules and some cytokine receptors. Ig superfamily cell adhesion molecules constitute over 100 molecules in vertebrates, and include NCAMs (neural cell adhesion molecules), L1 family CAMs, ICAMS (intracellular cell adhesion molecules), VCAMS (vascular cell adhesion molecules), SIGLECs (sialic acid binding Ig-like lectins, including CD22 and CD83), nectins, CD2, CD48.
The immunoglobulin superfamily molecule CADM1 was initially characterized by multiple research groups; as a result the molecule is identified by many names in scientific literature including cell adhesion molecule 1, synaptic cell adhesion molecule (synCAM), spermatogenic immunoglobulin superfamily molecule (sgIGSF), IGSF4, BL2, ST17, NECL2, RA175, and CADM1A. Initially reported to further act as a tumor suppressor, it is also known as TSLC1 (Murakami et al., Nature Genetics 27(4):427 (2001)).
Unlike cadherins and integrins, which require divalent cations such as Ca+2 or Mg+2 for adhesive activities, Ig superfamily molecules are typically Ca+2 or Mg+2 independent. The CADM1 structure is characterized as having an extracellular domain with three immunoglobulin-like motifs, a single hydrophobic membrane-spanning α helix and an intracellular domain that binds actin fibers via DAL-1, and a short C-terminal cytoplasmic tail containing a PDZ-binding motif. Two CADM1 isoforms are known, NM—014333 and NM—001098517, the latter having a 27 amino acid deletion. Analysis indicates that the amino acid sequences corresponding to the cytoplasmic domain of CADM1 are identical in five mammals and highly conserved in vertebrates, suggesting an important role of CADM1 in normal cell-cell interaction. The mouse CADM1 orthologue (AAQ023810) shows 97% identity to the human CADM1. (Fukami et al., Gene 295:7-12 (2002)).
CADM1 is expressed in nerves and mast cells (Ito et al. J Pharmacol Sci.; 102(1):1-5 (2006)), pulmonary alveolar cells (Ito et al. Histol Histopathol. 18(4):1321-9 (2003)), pancreatic secretory cells (Shingai et al. J Biol Chem.; 278(37):35421-7 (2003)), (Wakayama et al., Blood; 101(7):2601-8 (2003)). It is also associated with hepatocellular carcinoma (HCC). CADM1 appears to be expressed in fetal and cirrhotic adult bile duct cells, but is absent from disease-free adult bile ducts (Ito et al., Hepatology; 45(3):684-94 (2007)). It is further reported to be associated with glioblastomas and lung cancer.
Two mechanisms resulting in CADM1 inactivation have been identified: through promoter methylation, and through loss of heterozygosity at the gene locus. Methylation of the CADM1 promoter reportedly results in loss of CADM1 expression in tumors, including lung esophageal, pancreatic, breast, and prostate cancers, particularly in tumors with aggressive behavior. (Murakami et al., Mol Cancer. 4:28 (2005)).